Obstructive sleep apnea (OSA) with daytime hypersomnolence is present in at least 2-4% of adults in developed countries. OSA may affect more than 50% of individuals over the age of 65, and significant depressive symptoms may be present in as many as 26% of a community-dwelling population of older adults. This disorder manifests as repeated events of sleep state-dependent reductions in upper airway dilator motoneuronal activity with consequent upper airway occlusions and oxyhemoglobin desaturations, each terminating with abrupt arousal and reoxygenation. The hypoxia and reoxygenation events may occur as frequently as once every minute of sleep. Despite therapy to alleviate obstructive sleep apnea events, many individuals with OSA have residual sleepiness. Mechanisms of the residual hypersomnolence in persons with OSA are not understood, but severity of hypoxemia in OSA predicts, in part, severity of hypersomnolence.
Long-term intermittent hypoxia in mice, modeling the patterns of hypoxia/reoxygenation observed in moderate-severe sleep apnea, results in protracted hypersomnolence and hippocampus-dependent memory impairments with significant oxidative modifications in many brain regions, including wake-active regions and the hippocampus. The oxidative modifications observed following hypoxia/reoxygenation in wake-active neural groups that might contribute to impaired wakefulness and hypersomnolence include nitration, lipid peroxidation and carbonylation (7, 8, 12). Inducible nitric oxide synthase (iNOS) contributes to nitration and lipid peroxidation injuries in the intermittent hypoxia model of sleep apnea; however, transgenic absence of iNOS function does not confer resistance to intermittent hypoxia carbonylation injury and bestows only partial resistance on the proinflammatory gene response. A source of oxidation injury from long-term hypoxia/reoxygenation should be identified.
NADPH oxidase-dependent production of superoxide radical (O2−.) has been identified as a major contributor to oxidative injury in the brain under conditions of both inflammation and severe hypoxia/reperfusion injury. Moreover, NADPH oxidase has been implicated in oxidative neurodegeneration, including Alzheimer's disease and in dopaminergic neuronal injury in murine models of Parkinson's disease. NADPH oxidase has been identified in select populations of neurons, raising the possibility that neuronal NADPH oxidase activation could contribute to enhanced neuronal vulnerability to oxidative injury. Presently, it is unknown whether NADPH oxidase is present in wake-active neurons, whether intermittent hypoxia that models sleep apnea increases NADPH oxidase in regions with wake-active neurons, or whether NADPH oxidase might mediate the intermittent hypoxia-induced hypersomnolence, oxidative injury and/or proinflammatory responses.